Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
  • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
  • A61K31/37—Coumarins, e.g. psoralen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
  • C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
  • C07D311/46—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring
  • C07D311/48—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring with two such benzopyran radicals linked together by a carbon chain

Definitions

• the invention relates to novel (m-s-ulfamidobenzylidene)-3,3-bis (4-hydroxycoumarin) compounds of the formula wherein R and R are selected from the group consistting of hydrogen, an alkyl having 1 to 8 carbon atoms, an aryl and an aralky-l wherein the alkyl has 1 to 4 car-
• R and R are selected from the group consistting of hydrogen, an alkyl having 1 to 8 carbon atoms, an aryl and an aralky-l wherein the alkyl has 1 to 4 car-
• the invention also relates to a novel process of their preparation and novel intermediates.
• the invention further relates to novel uricosuric compositions and to a method of promoting uricosuria.
• novel compounds of Formula I and their alkali metal salts possess interesting pharmacological properties, particularly uricosuric activity without undesirable side effects. They are useful for the treatment of chronic gout, hyperuricemia, and gouty rheumatism. They can be, in addition, employed during a treatment with penicillin or P.A.S. as adjunctive medication, in hibiting tu'bulary excertion of these medicines.
• novel (m-sulfamidobenzylidene)-3,3'bis-(4-hydrodroxycoumarin) compounds of the invention are selected from the group consisting of compounds of the formula SOzN (I) wherein R and R are selected from the group consistting of hydrogen, an alkyl having 1 to 8 carbon atoms,
• alkyl has 1 to 4 carbon atoms and their alkali metal salts.
• the meta-sulfamidobenzaldehydes of Formula 11 which serve as starting materials in the present process, can be prepared starting from a derivative of metato luenesulfonic acid such as the corresponding acid chloride or amide.
• a derivative of metato luenesulfonic acid such as the corresponding acid chloride or amide.
• m-sulfamidobenzaldehyde preferably m-toluenesulfamide is oxidized with chromic acid anhydride inthe presence of a mixture of acetic acid anhydride and acetic acid to form the diacetate of meta-sulfamidobenzaldehyde which by acid hydrolysis furnishes the desired meta-sulfamidobenzaldehyde.
• m-toluenesulfochloride is preferably chosen as the starting material, which is oxidized with chromic acid anhydride in the presence of a mixture of acetic acid anhydride and acetic acid into the diacetate of benzaldehyde metasulfochloride and the latter compound is then condensed with the desired amine such as diethylamine followed by acid hydrolysis to obtain the desired benzaldehyde such as m-N,N-diethylsulfamidobenzaldehyde.
• alkyl amines and dialkyl amines wherein the alkyl radicals have 1 to 8 carbon atoms such as ethyl amine, methyl amine, butyl amine, isoaryl amine, methylethyl amine, dibutyl amine, etc.; aryl amines such as aniline, N-methyl aniline, etc.; aralkyl amines such as benzyl amine, dilbenzyl amine, phenethyl amine, N-ethyl benzyl amine, etc.
• novel uricosuric compositions of the invention are comprised of a compound selected from the group consisting of (m-sulfamidobenzylidene)-3,3'bis-(4-hydroxycoumarins) of the formula OH OH wherein R and R are selected from the group consisting of hydrogen, an alkyl having 1 to 8 carbon atoms, an aryl and an aralkyl wherein the alkyl has 1 to 4 carbon atoms and their alkali metal salts and a major amount of a pharmaceutical carrier.
• the said compositions can be prepared in the form of tablets, sugar coated pills, gelatin drops, granules and syrups prepared in the usual manner.
• the novel method of promoting uricosuria in warmblooded animals comprises administering an effective amount of a compound selected from the group consisting of a (m sulfamidobenzylidene)-3,3'-bis-(4-hydr'oxycoumarin) of the formula wherein R and R are selected from the group consisting of hydrogen, an alkyl having 1 to 8 carbon atoms, an aryl and an aralkyl wherein the alkyl has 1 to 4 carbon atoms and their alkali metal salts.
• the said products may be administered orally and the usual daily dosage is between 500 mg. and 2 gm. in the adult depending upon the therapeutic utilization (uricosuric or adjunctive medication of a treatment with penicillin or P.A.S.).
• the meta-sulfamidobenzaldehyde occurred in the form of colorless platelets soluble in alcohol and acetone, in 20 volumes of water with recrystallization and slightly soluble in ether, benzene and chloroform.
• Step. B Preparation of (meta-sulfamidobenzylia'ene)- 3,3'-bis- (4-hydr0xyc0umarin).-3 gm. of meta-sulfiamidobenzaldehyde and 100 cc. of water were heated to C. while agitating the mixture and then 5.25 gm. of 4- hydroxycoumarin were added while continuing the heating and agitation for a period of two hours. The reaction mixture was then cooled and iced and the residue was vacuum filtered, washed by trituration with water and dried under vacuum. The product was purified by recrystallization from 10 volumes of benzyl alcohol.
• the precipitate was dissolved in an aqueous alkaline solution and the solution was filtered through carbon black and acidified with hydrochloric acid. The precipitate was vacuum filtered, washed with water and dried under vacuum to obtain 4.5 gm. of (meta-sulfamidobenzylidene)- 3,3-bis-(4-hydroxycoumarin) having a melting point of The product occurred in the form of colorless prisms soluble in dilute aqueous alkalis and insoluble in water, alcohol, ether, acetone, benzene and chlorform.
• Step B Preparation of m-N,N-diethylsulfamiaob-enzaldehyde.22 gm. of the diacetate of m-sulfochloride benzaldehyde were introduced into cc. of anhydrous benzene and the solution was cooled to about 5 C. Then in a space of an hour and a half, a solution of 16 cc. of diethylamine and 16 cc. of anhydrous benzene were added and the reaction mixture was agitated While cooling slightly for a period of three hours. Then the diethylamine hydrochloride formed was removed by filtration and the benzenic solution was evaporated to dryness to obtain 19.5 gm.
• Step C Preparation of (meta-N,N-diethyZsulfamidobenzylidene) 3,3 bis-(4-hydr0xycoumarin).
• m-N,N-diethylsulfamidobenzaldehyde was condensed with 4-hydroxycouman'n to obtain a 50 to 60% yield of (m-N,N-diethylsulfamidobenzylidene -3 ,3 '-bis- (4-hydroxycoumarin) 'having a melting point of 221i-1 C.
• Table II gives the results obtained after oral administration.
• the plasmatic P.S.P. was determined spectrophotometrically on blood samples taken from the ophthalmic plexus 10, and 60 minutes after its administration. (Samples of about 0.2 cc. of blood were recovered in a heparinated microtube.)
• the products were placed in suspension in gum syrup diluted in half.
• phenylbutazone was utilized in a specialized injectable form (Geigy).
• (Meta sulfamildobenzylidene) 3,3 bis-(4-hydroxycoumarin) was utilized in solution in 0.1 N sodium hydroxide solution after adjustment to a pH of 9. Table I gives the results obtained after subcutaneous administration.
• Time of coagulation of the blood The time of prothrombine (Quick time) was determined by the micromethod of Soulier. A sample of 3 drops of blood from the marginal vein of the ear of the rabbit was deposited on a microscope slide. One drop of aqueous suspension of thromboplastine was added to each drop of the blood and the time for coagulation at room temperature was determined. The average of the times observed for the three drops was reported as the time of coagulation of the blood of the animal tested. In a normal rabbit, this time was from 30 to 40 seconds. (m-Su-lfamidobenzylidene)-3,3-bis-(4-hydroxycoumarin) utilized in aqueous suspension was administered orally at a single dose of 7 50 mgjkg. to a group of male rabbits of 3 kg. A group of control rabbits received distilled water. The Quick time was determined before the treatment, then 1, 2 and 3 days after. The results in Table V were obtained:

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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  • BE BE648894D patent/BE648894A/xx unknown
  • GB GB1050933D patent/GB1050933A/en active Active
• 1963
  • 1963-06-05 FR FR937077A patent/FR2746M/fr active Active
  • 1963-09-05 FR FR946680A patent/FR1453223A/fr not_active Expired
• 1964
  • 1964-05-12 CH CH614864A patent/CH415679A/fr unknown
  • 1964-05-22 NL NL6405788A patent/NL6405788A/xx unknown
  • 1964-05-26 US US370363A patent/US3243443A/en not_active Expired - Lifetime
  • 1964-06-05 DE DE19641793283 patent/DE1793283A1/de active Pending
  • 1964-06-05 DE DER38075A patent/DE1299000B/de active Pending

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